Due to good biocompatibility, calcium phosphates (hereinafter, referred to as “CaP”), as represented by hydroxyapatite (hereinafter, referred to as “HAp”), are of great interest as biomaterials. For example, calcium phosphates (CaP), and hydroxyapatite (HAp) in particular, have been used as artificial joints, bone fillers, artificial bones, dental implants, percutaneous devices, and dental filler cements. Further, in order to render bioactivity to a high-molecular medical material such as silicone rubber and polyurethane, calcium phosphate (CaP) such as hydroxyapatite (HAp) is often bonded to such a high-molecular medical material. Other uses include a filler for chromatography.
When using hydroxyapatite (HAp) or other types of calcium phosphates (CaP) by bonding it to medical material or high-molecular medical material, or when using hydroxyapatite (HAp) or calcium phosphate (CaP) as a filler for chromatography, it is preferable that these materials be used in sintered form, i.e., in the form of ceramic, in order to improve stability and ensure formability in the body. Further, for uniform coating of the high-molecular medical material and improved resolution in chromatography, a small and uniform particle diameter (narrow particle size distribution) is needed.
Common methods of producing particles of hydroxyapatite (HAp) and other types of calcium phosphates (CaP) include a wet method, a hydrothermal method, and a dry method, for example. The wet method is predominant in industrial settings since it allows for mass synthesis. Specific examples of the wet method are described, for example, in Non-Patent Publication 1, which teaches a precipitation method in which phosphoric acid is dropped into a slurry of calcium hydroxide to produce calcium phosphate, and a hydrolysis method in which calcium phosphate is produced by the reaction of calcium phosphate dihydrate with calcium carbonate.
There is also a method in which particles of calcium phosphate (Cap) is dried to produce sintered particles (ceramic particles). This can be carried out by heating at 800° C. to 1200° C., or by a spray drying method, for example, as disclosed in Non-Patent Publications 2 and 3. The spray drying method is a technique in which a dispersion of particles, such as a solution or suspension (slurry, etc.) containing effective substance is atomized and the particles are instantly solidified by bringing it into contact with a stream of hot air. More specifically, a solution or suspension containing primary particles of calcium phosphate (CaP) is sprayed in a stream of hot air to form fine spherical particles of calcium phosphate.
Non-Patent Publication 4 describes a method in which a source solution containing calcium phosphate is dropped into liquid nitrogen to prepare particles of calcium phosphate, which are then sintered to produce sintered particles of calcium phosphate. This publication also describes sintered particles of calcium phosphate, obtained by this method, whose particle diameter ranges from 450 μm to 3000 μm.
Non-Patent Publication 5 describes a method in which a drip-casting process is used to prepare hydroxyapatite particles, which are then sintered to produce sintered particles of hydroxyapatite. This publication also describes sintered particles of hydroxyapatite, obtained by this method, whose particle diameter ranges from 0.7 mm to 4 mm.
[Non-Patent Publication 1]
Inorganic Materials, Vol 2 No. 258, 393-400 (1995), Controlling Morphology of Crystals and Crystal Groups of Hydroxyapatite and Related Phosphates, Nobuyuki Matsuda, Jo Wakana, Fumihiro Kaji
[Non-Patent Publication 2]
P. Luo and T. G. Nieh Biomaterials, 17, 1959 (1996), Preparing hydroxyapatite powders with controlled morphology 
[Non-Patent Publication 3]
L. J. Cummings, P. Tunon, T. Ogawa, Spec. Publ. R. Soc. Chem. 158, 134 (1994), Macro-Prep Ceramic Hydroxyapatite—New Life for an Old Chromatographic Technique 
[Non-Patent Publication 4]
Biomaterials 1994, Vol. 15 No. 6, M. Fabbri, G. C. Celotti and A. Ravaglioli, Granulates based on calcium phosphate with controlled morphology and porosity for medical applications: physico-chemical parameters and production technique 
[Non-Patent Publication 5]
Biomaterials 1996, Vol. 17 No. 20, Dean-Mo Liu, Fabrication and characterization of porous hydroxyapatite granules 
The inventors of the present invention have been conducting a study on the synthesis of a chemically bonded hydroxyapatite (HAp)-polymer complex, intended for the development of biocompatible devices for use in bio-tissues, and subcutaneous cells and other soft tissues in particular. In this connection, the inventors have produced monocrystalline hydroxyapatite particles (ceramic particles) by sintering (pre-baking) at 800° C. This was intended to improve crystallinity of the hydroxyapatite (HAp) for the purpose of suppressing the particles from dissolving and decomposing in the body. In order for the hydroxyapatite (HAp) particles to form strong chemical bonds on the surface of the high-molecular substrate, the particles need to be well dispersed in the medium when adsorbed by the high-molecular substrate. A problem, however, is that the hydroxyapatite (HAp) particles (primary particles) fuse together during the sintering process to form irregular secondary particles. This has resulted in lower dispersibility and a reduced specific surface area.
The problem of irregular secondary particles, lower dispersibility and reduced specific surface area also occurs in the method (spray drying method) disclosed in, for example, Non-Patent Publications 2 and 3. Further, with the spray drying method, the particle diameter of the calcium phosphate (CaP) particles cannot be controlled to a uniform size (particle size distribution cannot be narrowed beyond a certain range). To describe more specifically, in the spray drying method, a solution or suspension of particles is atomized in a stream of hot air, and this causes the fine particles (primary particles) of calcium phosphate (CaP) to fuse together and form secondary particles. Since it is impossible to control the number of fine particles (primary particles) that cluster together in the stream of hot air, it is not possible with the spray drying method to accurately control the particle size distribution of calcium phosphate (CaP) particles. Thus, when the spray drying method is used to produce ceramic particles of calcium phosphate (CaP), the resulting particles need to be further classified depending on intended use. For example, in the case where the ceramic particles of calcium phosphate (CaP) are used as a filler for chromatography, the support needs to have a uniform particle diameter (narrow particle size distribution) for improved resolution. Thus, when using ceramic particles of calcium phosphate (CaP) as a filler for chromatography, a ceramic particle group of calcium phosphate (CaP) needs to be used that has a uniform particle diameter (narrow particle size distribution).
Further, with the producing method of a ceramic particle group of calcium phosphate as disclosed in, for example, Non-Patent Publications 2 and 3, the resulting particle group cannot have a particle diameter smaller than 1 to 8 μm (Non-Patent Publication 2). Further, obtaining a particle group of a narrow particle size distribution by classifying the ceramic particle group of calcium phosphate disclosed in Non-Patent Publication 2 is not feasible due to physical limitations. Indeed, it is very difficult to reduce the particle size distribution any further and classification requires large cost.
The present invention was made in view of the foregoing problems, and an object of the invention is to provide a ceramic particle group that is dispersed in a solvent as primary particles of single crystal, and particularly a calcium phosphate (CaP) sintered particle group (ceramic particle group), as represented by monocrystalline hydroxyapatite (HAp), that is biocompatible, connective and adherent to biological tissues, and that is not easily decomposed and absorbed in the body, and that is useful as medical materials. The invention also provides to a producing method of such a particle group, and use thereof.